One of the most challenging problems of organic and medicinal chemistry is control of stereochemistry in the synthesis of important classes of natural products and medicinal agents, including antibiotics such as macrolides, ionophores, and beta-lactams. The goal of this project is to design strategies for stereo- and regiochemical control in the crucial C-C bond- forming process of the aldol reaction, and then to investigate the structural and mechanistic origins of the novel properties of these systems. The specific aims are (1) to investigate structural analogs of a titanium enolate previously investigated in this laboratory, which gives very high diastereofacial selectivities, including in-depth structural and mechanistic studies; (2) to investigate mechanistically a new camphor-based N-acyloxazolidinone synthesized in this laboratory, to determine why this substrate gives high selectivities for the chelation control product with both lithium and titanium, even though simpler analogues give low selectiveness with lithium, and to optimize its selectivities; (3) to extend the reactivity studies on alpha-alkoxy ketones recently carried out in this laboratory, including conformational and stereochemical factors, to find out why the titanium enolate selectivity is unexpectedly lower than that of more reactive lithium enolate, and to examine alpha- alkoxyaldehydes; (4) to develop ligand control of selectivity using chiral ligands, including novel, proposed tridentate ligands; and (5) to develop alkoxide bridging as a means of stereocontrol. Metal bridging specifically designed for control of selectivity constitutes a fertile area for investigation. Realization of these aims will provide new strategies and reagents for stereocontrolled synthesis as well as progress on fundamental structural and mechanistic questions. Of equal importance, we also expect these results to provide a fertile background for future studies on uses of metal bridging for stereocontrol in other reactions. Experimental tools such as 500-MHz NMR, X-ray crystallographic structure determination, HPLC, and capillary-column GLC make the necessary structure determinations and analyses of rates and selectivities, such as ratios of diastereomeric products, feasible now-even for complex molecules. Current medicinal chemistry provides ample evidence that the enantiomers of many medicinal agents are not inert but have different physiological effects. A fine-tuned, unequal mixture of enantiomers has even been utilized as a drug with greatly reduced side effects compared with the racemic material. Hence, stereocontrolled production of nonracemic substances is a crucial goal in current medicinal chemistry.